Quantitative Analysis to Support Full Extrapolation of Efficacy in - - PowerPoint PPT Presentation

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Quantitative Analysis to Support Full Extrapolation of Efficacy in Children for Partial Onset Seizures in Adjunctive Setting: FDA-PEACE Initiative Shailly Mehrotra Center for Translational Medicine, UMD; ORISE Fellow, FDA Division of Neurology

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Quantitative Analysis to Support Full Extrapolation of Efficacy in Children for Partial Onset Seizures in Adjunctive Setting: FDA-PEACE Initiative

Shailly Mehrotra Center for Translational Medicine, UMD; ORISE Fellow, FDA

M-CERSI-FDA WORKSHOP: QUANTITATIVE ASSESSMENT OF ASSUMPTIONS TO SUPPORT EXTRAPOLATION OF EFFICACY IN PEDIATRICS, 06/01/2016

Office of Clinical Pharmacology, FDA Division of Neurology Products, FDA

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Disease is similar

Disclaimer

M-CERSI-FDA WORKSHOP: QUANTITATIVE ASSESSMENT OF ASSUMPTIONS TO SUPPORT EXTRAPOLATION OF EFFICACY IN PEDIATRICS, 06/01/2016

The views expressed in this presentation do not necessarily represent the policies of the Food and Drug Administration or the Department of Health and Human Services.

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SLIDE 3

Disease is similar

Evidence to Support “Full Extrapolation” of Efficacy

Full Extrapolation

M-CERSI-FDA WORKSHOP: QUANTITATIVE ASSESSMENT OF ASSUMPTIONS TO SUPPORT EXTRAPOLATION OF EFFICACY IN PEDIATRICS, 06/01/2016

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SLIDE 4

Disease Similarity Between Adults & Children

  • PEACE/DNP provided the clinical expertise to describe:

– the pathophysiology of partial onset seizures (POS)

  • After excluding children under age 4 and those with

POS associated with epileptic encephalopathies such as Lennox-Gastaut, the pathophysiology of POS is similar in children (≥ 4year old) and adults.

M-CERSI-FDA WORKSHOP: QUANTITATIVE ASSESSMENT OF ASSUMPTIONS TO SUPPORT EXTRAPOLATION OF EFFICACY IN PEDIATRICS, 06/01/2016

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SLIDE 5

List of Drugs Investigated

Drug Population Mechanism of Action

Oxcarbazepine (Trileptal) ≥ 2 year

Blocks voltage dependent Na channels, increase K conductance and modulate high voltage activated Ca channels

Levetiracetam (Keppra) ≥ 1 month

Acts by binding to SV2A protein

Lamotrigine (Lamictal) ≥ 2 year

Inhibits voltage sensitive Na channels, stabilize neuronal membranes and modulates presynaptic release of excitatory neurotransmitter

Topiramate (Topamax) ≥ 2 year

Blocks voltage dependent Na channels, augments GABA activity, antagonize AMPA/Kainate subtype

  • f glutamate receptor, inhibits carbonic anhydrase

enzyme

Gabapentin (Neurontin) ≥ 3 years

Not known; binds with α2δ subunit of voltage activated calcium channel but therapeutic effects of binding are unknown

Perampanel (Fycompa) ≥12 year

Noncompetitive antagonist of AMPA glutamate receptor

Tiagabine (Gabitril) ≥12 year

Not known, enhances the activity of GABA an inhibitory neurotransmitter

Vigabatrin (Sabril) ≥10 year

Not known, increase levels of GABA in CNS

M-CERSI-FDA WORKSHOP: QUANTITATIVE ASSESSMENT OF ASSUMPTIONS TO SUPPORT EXTRAPOLATION OF EFFICACY IN PEDIATRICS, 06/01/2016

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CFB: Change from baseline

Plasma samples are collected in the maintenance phase

Primary Endpoint Median %CFB in Seizure Frequency/28 days in the DB Phase

X mg 2X mg 3X mg 3X mg PB PB Placebo (PB) PB Baseline Phase Titration Phase Maintenance Phase Double Blind (DB) Phase Randomization End of the trial Concomitant AEDs Concomitant AEDs 8-12 weeks 1-3 Concomitant AEDs 2-6 weeks 12-24 weeks

Trial Design and Primary Endpoint in Approval of AEDs in Adjunctive Setting

M-CERSI-FDA WORKSHOP: QUANTITATIVE ASSESSMENT OF ASSUMPTIONS TO SUPPORT EXTRAPOLATION OF EFFICACY IN PEDIATRICS, 06/01/2016

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SLIDE 7

Disease is similar

Evidence to Support “Full Extrapolation” of Efficacy

Full Extrapolation

M-CERSI-FDA WORKSHOP: QUANTITATIVE ASSESSMENT OF ASSUMPTIONS TO SUPPORT EXTRAPOLATION OF EFFICACY IN PEDIATRICS, 06/01/2016

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SLIDE 8

Source: Labels for oxcarbazepine, perampanel and levetiracetam

Observed Efficacy of Approved AEDs in Adults & Children from Registration Trials

Adult Children

Placebo Corrected Median % CFB in Seizure Frequency/28 days

Children : Children : Children :

M-CERSI-FDA WORKSHOP: QUANTITATIVE ASSESSMENT OF ASSUMPTIONS TO SUPPORT EXTRAPOLATION OF EFFICACY IN PEDIATRICS, 06/01/2016

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SLIDE 9

9 Source: Labels for topiramate, lamotrigine and gabapentin

Observed Efficacy of Approved AEDs in Adults & Children from Registration Trials

Adult Children

Placebo Corrected Median % CFB in Seizure Frequency/28 days

Children : Children : Children :

M-CERSI-FDA WORKSHOP: QUANTITATIVE ASSESSMENT OF ASSUMPTIONS TO SUPPORT EXTRAPOLATION OF EFFICACY IN PEDIATRICS, 06/01/2016

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Disease is similar

Evidence to Support “Full Extrapolation” of Efficacy

Full Extrapolation

M-CERSI-FDA WORKSHOP: QUANTITATIVE ASSESSMENT OF ASSUMPTIONS TO SUPPORT EXTRAPOLATION OF EFFICACY IN PEDIATRICS, 06/01/2016

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SLIDE 11
  • Cmin: trough concentration at steady state
  • Cavg: average concentration at steady state
  • Same metric utilized between adults and children for a

given drug

11

Concentration Metric Utilized for Comparing Exposures in Adults and Children

M-CERSI-FDA WORKSHOP: QUANTITATIVE ASSESSMENT OF ASSUMPTIONS TO SUPPORT EXTRAPOLATION OF EFFICACY IN PEDIATRICS, 06/01/2016

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SLIDE 12

*Doses in the boxes denote highest recommended maintenance doses

Concentrations at Approved Doses in Adults & Children

Adults Children

Concentration

Drug A Drug B Drug C Drug D

Concentration Concentration Concentration

Doses Doses Doses Doses

M-CERSI-FDA WORKSHOP: QUANTITATIVE ASSESSMENT OF ASSUMPTIONS TO SUPPORT EXTRAPOLATION OF EFFICACY IN PEDIATRICS, 06/01/2016

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SLIDE 13

Disease is similar

Evidence to Support “Full Extrapolation” of Efficacy

Full Extrapolation

M-CERSI-FDA WORKSHOP: QUANTITATIVE ASSESSMENT OF ASSUMPTIONS TO SUPPORT EXTRAPOLATION OF EFFICACY IN PEDIATRICS, 06/01/2016

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Methodology

a) Graphical Analysis b) Model Based Analysis

M-CERSI-FDA WORKSHOP: QUANTITATIVE ASSESSMENT OF ASSUMPTIONS TO SUPPORT EXTRAPOLATION OF EFFICACY IN PEDIATRICS, 06/01/2016

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Drug A Exposure-Response in Adults & Children

Mean % CFB in Seizure Frequency/28 days Concentration

Log (% CFB in Seizure Frequency/28 days)

Concentration Log ( % CFB in Seizure Frequency/28 days)

Doses

Adults Children

M-CERSI-FDA WORKSHOP: QUANTITATIVE ASSESSMENT OF ASSUMPTIONS TO SUPPORT EXTRAPOLATION OF EFFICACY IN PEDIATRICS, 06/01/2016

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Drug B Exposure-Response in Adults & Children

Adults Children

% CFB in Seizure Frequency/28 days

% CFB in Seizure Frequency/28 days Mean % CFB in Seizure Frequency/28 days Concentration Concentration

Doses

M-CERSI-FDA WORKSHOP: QUANTITATIVE ASSESSMENT OF ASSUMPTIONS TO SUPPORT EXTRAPOLATION OF EFFICACY IN PEDIATRICS, 06/01/2016

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SLIDE 17

Drug G Exposure-Response in Adults & Children

Adults Children

M-CERSI-FDA WORKSHOP: QUANTITATIVE ASSESSMENT OF ASSUMPTIONS TO SUPPORT EXTRAPOLATION OF EFFICACY IN PEDIATRICS, 06/01/2016

Normalized Dose (mg)

Predicted seizure rate during maintenance phase

Drug G

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SLIDE 18

18

Evidence Gathered from AEDs Approved Between 1960-1980

  • Generally acceptable therapeutic range of total

carbamazepine in plasma (i.e. 4-12 µg/mL) is the same in adult and children

Carbamazepine

  • Dose in pediatrics was selected such that it produces

plasma concentration within the generally accepted therapeutic target of 10-20 µg/mL, which is same for adults

Phenytoin

  • Approved in ≥ 10 years age, same dose and the same

target therapeutic plasma concentration range (50 -100 µg/mL) are recommended.

Valproic acid

M-CERSI-FDA WORKSHOP: QUANTITATIVE ASSESSMENT OF ASSUMPTIONS TO SUPPORT EXTRAPOLATION OF EFFICACY IN PEDIATRICS, 06/01/2016

Source: Labels for carbamazepine, phenytoin and valproic acid

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SLIDE 19

Disease is similar

Quantitative Assessment of Response, Exposures and Exposure-Response Supports “Full Extrapolation” of Efficacy

Full Extrapolation

M-CERSI-FDA WORKSHOP: QUANTITATIVE ASSESSMENT OF ASSUMPTIONS TO SUPPORT EXTRAPOLATION OF EFFICACY IN PEDIATRICS, 06/01/2016

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Required information to Support an Indication for the Treatment of POS in Patients ≥ 4 years

  • Approved indication for the treatment of POS in adults.
  • A pharmacokinetic analysis to determine a dosing regimen

that provides similar drug exposure (at levels demonstrated to be effective in adults) in pediatric patients 4 years of age and

  • lder and in adult patients with POS. This analysis will require

pharmacokinetic data from both the adult and children (4 years of age and older) populations.

  • Long-term open-label safety study(ies) in pediatric patients 4

years of age and older.

M-CERSI-FDA WORKSHOP: QUANTITATIVE ASSESSMENT OF ASSUMPTIONS TO SUPPORT EXTRAPOLATION OF EFFICACY IN PEDIATRICS, 06/01/2016

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SLIDE 21
  • UMD:

– Tao Liu (ORISE Fellow) – Joga Gobburu

  • PEACE:

– Jack Pellock – Neil D’Cruz – Jackie French

  • Epilepsy Foundation:

– Angela Ostrom

  • Sponsors for providing data
  • FDA review teams

Acknowledgements

M-CERSI-FDA WORKSHOP: QUANTITATIVE ASSESSMENT OF ASSUMPTIONS TO SUPPORT EXTRAPOLATION OF EFFICACY IN PEDIATRICS, 06/01/2016

  • FDA:

– OCP:

  • Angela Men
  • Atul Bhattaram
  • Mehul Mehta
  • Ramana Uppoor
  • Michael Bewernitz
  • Vikram Sinha*
  • Kevin Krudys
  • Joo Yeon Lee

– DNP:

  • Billy Dunn
  • Eric Bastings
  • Norman Hershkowitz
  • Philip Sheridan
  • Cathleen Michaloski
  • DPMH:
  • Donna Snyder
  • Hari Sachs

* Currently at Merck